Actomyosin-II protects axons from degeneration induced by mild mechanical stress.

Whether, to what extent, and how the axons in the central nervous system (CNS) can withstand sudden mechanical impacts remain unclear. By using a microfluidic device to apply controlled transverse mechanical stress to axons, we determined the stress levels that most axons can withstand and explored their instant responses at nanoscale resolution. We found mild stress triggers a highly reversible, rapid axon beading response, driven by actomyosin-II-dependent dynamic diameter modulations. This mechanism contributes to hindering the long-range spread of stress-induced Ca2+ elevations into non-stressed neuronal regions. Through pharmacological and molecular manipulations in vitro, we found that actomyosin-II inactivation diminishes the reversible beading process, fostering progressive Ca2+ spreading and thereby increasing acute axonal degeneration in stressed axons. Conversely, upregulating actomyosin-II activity prevents the progression of initial injury, protecting stressed axons from acute degeneration both in vitro and in vivo. Our study unveils the periodic actomyosin-II in axon shafts cortex as a novel protective mechanism, shielding neurons from detrimental effects caused by mechanical stress.

MRI-based radiomic models for the preoperative prediction of extramural venous invasion in rectal cancer: A systematic review and meta-analysis.

AIM: To estimate the diagnostic value of magnetic resonance imaging (MRI)-based radiomic models in detecting the extramural venous invasion (EMVI) of rectal cancer. MATERIALS AND METHODS: Appropriate studies in multiple electronic databases were systematically retrieved. The Quality Assessment of Diagnostic Accuracy Studies 2 and Radiomics Quality Score (RQS) were used to evaluate the eligible studies' methodology quality. Summary accuracy metrics were calculated, and the publication bias was detected using Deek's funnel plot. The sensitivity and meta-regression analysis were performed to investigate the causes of heterogeneity. RESULTS: For the seven eligible studies, which included 1175 patients, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.80 (95 % CI, 0.70-0.88), 0.89 (95 % CI, 0.84-0.92), 7.0 (95 % CI, 4.7, 10.4), 0.22 (95 % CI, 0.14, 0.34), and 32 (95 % CI, 16, 65), respectively. The area under the receiver operating characteristic curve (AUC) was 0.91 (95 % CI, 0.88, 0.93). Moderate heterogeneity was found due to I2 values of 38.63 % and 32.29 % in sensitivity and specificity, respectively. Meta-regression analysis suggested that the patient enrollment, number of patients, segmentation method, and RQS score were the source of the heterogeneity. The head-to-head analysis suggested that radiomics model had a higher sensitivity for detection of EMVI than subjective evaluation by radiologist (0.47 vs. 0.73, p ≤ 0.001). CONCLUSION: Our study suggests that MRI-based radiomic models have good diagnostic value in detecting EMVI for rectal cancer patients. Nevertheless, more prospective and high-quality studies with larger sample sizes are needed in the future to validate these results.

Serum Homer1 is a Novel Biomarker for Predicting the Clinical Outcomes of Acute Ischemic Stroke Patients.

Purpose: We aim to explore the relationship between Homer1 and the outcomes of AIS patients at 3 months. Patients and Methods: This prospective cohort study was conducted from May 2022 to March 2023. In this study, we investigated the association between serum Homer1 levels by enzyme-linked immunosorbent assay at admission and functional outcomes of patients at 3 months after AIS. Results: Overall, 89 AIS patients (48 good outcomes and 41 poor outcomes) and 83 healthy controls were included. The median serum Homer1 level of patients at admission with poor outcomes was significantly higher than that of patients with good outcomes (39.33 vs 33.15, P<0.001). Serum Homer1 levels at admission were positively correlated with the severity of AIS (r = 0.488, P<0.001). The optimal cutoff of serum Homer1 level as an indicator for an auxiliary diagnosis of 3 months functional outcomes was 35.07 pg/mL, with a sensitivity of 75.0% and a specificity of 92.7% (AUC 0.837; 95% CI [0.744-0.907]; P<0 0.001). The odds ratio of MRS > 2 predicted by the level of serum Homer1 after 3 months was 1.665 (1.306-2.122; P<0.001). Conclusion: Serum concentrations of Homer1 have a high predictive value for neurobehavioral outcomes after acute ischemic stroke. Higher serum Homer1 levels (>35.07 pg/mL) were positively associated with poor functional outcomes of patients 3 months post-stroke.

A novel role of acellular hemoglobin in hemolytic thrombosis.

BACKGROUND: Hemolytic thrombosis has been associated with acellular hemoglobin released from damaged red blood cells during hemolysis. However, the precise molecular mechanism underlying acellular hemoglobin-induced thrombosis remains arguable. In this study, we examined the interaction between hemoglobin and the A1 domain of von Willebrand factor (VWF), which is a critical mediator of platelet activation. METHODS: Previous studies have suggested that the interaction between hemoglobin and the A1 domain of VWF enhances VWF's hemostatic activity. We employed a multidisciplinary investigation to re-examine this interaction, and identified significant differences in binding affinity between the active and inactive forms of A1. RESULTS: We found that hemoglobin binds more strongly to the active A1 than the inactive form. Using hydrogen­deuterium exchange mass spectrometry, we identified the specific residues involved in this interaction, which are located on the α1-ß2 and ß3-α2 loops that are typically covered by the "autoinhibitory module" in the inactive A1. This observation provides a structural explanation for the differential binding affinity between the active and inactive forms of A1. We demonstrated that the binding of hemoglobin to A1 blocks the interaction between GPIbα and VWF, and inhibits VWF-mediated thrombosis in vivo. Furthermore, we found that administration of hemoglobin led to similar levels of thrombocytopenia and microthrombosis in both wildtype and VWF-deficient mice, indicating that the mechanism underlying acellular hemoglobin-induced thrombosis is VWF-independent. CONCLUSIONS: These findings challenge the previous theory that hemoglobin-induced thrombosis occurs solely through binding with VWF, and provide evidence supporting a novel role for hemoglobin in hemolytic thrombosis.

Machine learning reveals neutrophil-to-lymphocyte ratio as a crucial prognostic indicator in severe Japanese encephalitis patients.

Japanese encephalitis (JE) is a severe infectious disease affecting the central nervous system (CNS). However, limited risk factors have been identified for predicting poor prognosis (PP) in adults with severe JE. In this study, we analyzed clinical data from thirty-eight severe adult JE patients and compared them to thirty-three patients without organic CNS disease. Machine learning techniques employing branch-and-bound algorithms were used to identify clinical risk factors. Based on clinical outcomes, patients were categorized into two groups: the PP group (mRs ≥ 3) and the good prognosis (GP) group (mRs ≤ 2) at three months post-discharge. We found that the neutrophil-to-lymphocyte ratio (NLR) and the percentage of neutrophilic count (N%) were significantly higher in the PP group compared to the GP group. Conversely, the percentage of lymphocyte count (L%) was significantly lower in the PP group. Additionally, elevated levels of aspartate aminotransferase (AST) and blood glucose were observed in the PP group compared to the GP group. The clinical parameters most strongly correlated with prognosis, as indicated by Pearson correlation coefficient (PCC), were NLR (PCC 0.45) and blood glucose (PCC 0.45). In summary, our findings indicate that increased serum NLR, N%, decreased L%, abnormal glucose metabolism, and liver function impairment are risk factors associated with poor prognosis in severe adult JE patients.

Proteomic landscape subtype and clinical prognosis of patients with the cognitive impairment by Japanese encephalitis infection.

BACKGROUND: Cognitive impairment is one of the primary sequelae affecting the quality of life of patients with Japanese encephalitis (JE). The clinical treatment is mainly focused on life support, lacking of targeted treatment strategy. METHODS: A cerebrospinal fluid (CSF) proteomic profiling study was performed including 26 patients with JE in Gansu province of China from June 2017 to October 2018 and 33 other concurrent hospitalized patients who were excluded central nervous system (CNS) organic or CNS infection diseases. The clinical and proteomics data of patients with JE were undergoing combined analysis for the first time. RESULTS: Two subtypes of JE associated with significantly different prognoses were identified. Compared to JE1, the JE2 subtype is associated with lower overall survival rate and a higher risk of cognitive impairment. The percentages of neutrophils (N%), lymphocyte (L%), and monocytes (M%) decreased in JE2 significantly. CONCLUSIONS: The differences in proteomic landscape between JE subgroups have specificity for the prognosis of cognitive impairment. The data also provided some potential target proteins for treatment of cognitive impairments caused by JE. Trial registration ChiCTR, ChiCTR2000030499. Registered 1st June 2017, http://www.medresman.org.cn/pub/cn/proj/projectshow.aspx?proj=6333.

Tissue dynamics of von Willebrand factor characterized by a novel fluorescent protein-von Willebrand factor chimera.

BACKGROUND: Tissue dynamics of von Willebrand factor (VWF) that are vital to its biological function have not been fully characterized. OBJECTIVE: To develop a new fluorescent protein--VWF chimera (FP-VWF) that has similar hematologic function to wild-type VWF and use it to monitor the tissue dynamics of VWF distribution. METHODS: Genotyping, platelet counting, tail bleeding time assay, agarose gels, western blot, platelet aggregation, proteolytic analysis, and ELISA were applied in characterizing the function of FP-VWF; fluorescence spectrometer and confocal fluorescence microscope were used to monitor the plasma and tissue distribution of FP-VWF. RESULTS: The transgenic mice that carry the FP-VWF retain hematologic activity of VWF with plasma levels of FP-VWF reduced by 50% and there are reduced high molecular weight FP-VWF multimers compared to the wild-type mice. The GPIb-binding and ADAMTS-13 (A Disintegrin and Metalloprotease with ThrombSpondin type 1 motif, member 13) proteolytic efficiency of FP-VWF are similar to wild-type VWF. The tissue distribution of FP-VWF was probed directly through its intrinsic fluorescence at normal or stimulated status, which indicated that the medicine-stimulated endogenous FP-VWF seems primarily released from the aorta and cleared in the spleen. Similar results were observed in non-fluorescent mice through a standard immunofluorescence approach. The fluorescence signals of FP-VWF were also similar to the standard dye-based approach in detecting the FeCl3 -induced blood clotting in vivo. CONCLUSIONS: Together, these results suggest that this novel FP-VWF chimera is valuable in probing the tissue dynamics of VWF in quite a few biological and pharmaceutical applications.

Fatal contrast medium-induced adverse response to iohexol in carotid artery angioplasty: A case report.

RATIONALE: Adverse drug reactions (ADRs) to iohexol occur infrequently and generally result in good outcomes. This report describes a 51-year-old man suffering from an ADR to iohexol (Omnipaque 300), which proved fatal. PATIENT CONCERNS: The patient was admitted to hospital due to intermittent dizziness over 2 years and transient numbness and weakness of the right limbs for 1 week. The patient was investigated using carotid artery angioplasty (CAA), during which the patient suffered a sudden disorder of consciousness and a tonic-clonic seizure leading to status epilepticus. After the CAA, the patient suffered from increasing cerebral edema volume. DIAGNOSES: Results of digital subtraction angiography and computed tomography angiography performed at another hospital before the CAA suggested severe stenosis of the left internal carotid artery at the spinal C1 level. In the processes of intraoperative and postoperative CAA, the patient developed severe allergic reactions to the contrast agent including epilepsy, brain tissue edema, and renal failure, which were typical according to the 10th edition of the American College of Radiology Manual on Contrast Media (ACR Manual on Contrast Media, Version 10.3, 2017). INTERVENTIONS: The patient was treated with antiepileptic, antianaphylactic therapy, and control of blood pressure. Due to rapid and severe brain edema, a decompressive craniectomy was performed on the left side, but it was unsuccessful in reducing brain edema. Subsequently, the patient was started on continuous renal replacement therapy for progressive renal dysfunction. OUTCOMES: Despite the use of a variety of medical and surgical interventions, it was not possible to control the patient's condition, which gradually declined leading to death, 7 days post-CAA. LESSONS: To the authors' knowledge, this represents the 1st case of fatal contrast-induced ADR to iohexol during CAA. Although a variety of preoperative tests for iohexol allergy were performed according to recommendations from the ACR Manual on Contrast Media (Version 10.3, 2017), severe complications related to iodized contrast agent still occurred. If the ADR had been recognized sooner and decompressive craniectomy and continuous renal replacement therapy were applied earlier, it would have improved the patients' prognosis.

Voluntary exercise promotes neurotrophic factor and suppresses apoptosis in hippocampal ischemia.

Previous studies have demonstrated that exercise facilitates recovery from ischemia. However, the mechanisms need to be further elucidated. The current investigation was designed to study the effect of voluntary exercise on cerebral ischemia and discuss possible mechanisms usingmiddle cerebral artery occlusion model. Rats were randomly allocated to three groups: control, middle cerebral artery occlusion, and middle cerebral artery occlusion plus exercise. The middle cerebral artery occlusion plus exercise group was preconditioned by three weeks of voluntary wheel running prior to surgery. The accelerated rotarod test was employed to evaluate motor performance. Infarct volumes were analyzed to detect the neuroprotective effect of voluntary exercise. Brain-derived neurotrophic factor, Bax, Bcl-2, and caspase-3 protein expressions were measured by Western blot. Behavior evaluation showed the middle cerebral artery occlusion plus exercise group achieved significantly longer time on a rotarod than the unexercised group. Additionally, voluntary exercise reduced cerebral infarction and increased brain derived neurotrophic factor expression. Exercise down-regulated the apoptotic Bax/Bcl-2 ratio and caspase-3 protein expression. Results indicate that voluntary wheel running promote hippocampal brain derived neurotrophic factor and inhibit cell apoptosis in ischemia-induced impairment.

Perovskite solar cells: must lead be replaced - and can it be done?

Perovskite solar cells have recently drawn significant attention for photovoltaic applications with a certified power conversion efficiency of more than 22%. Unfortunately, the toxicity of the dissolvable lead content in these materials presents a critical concern for future commercial development. This review outlines some criteria for the possible replacement of lead by less toxic elements, and highlights current research progress in the application of low-lead halide perovskites as optically active materials in solar cells. These criteria are discussed with the aim of developing a better understanding of the physio-chemical properties of perovskites and of realizing similar photovoltaic performance in perovskite materials either with or without lead. Some open questions and future development prospects are outlined for further advancing perovskite solar cells toward both low toxicity and high efficiency.

Protective Effects of Colivelin Against Alzheimer's Disease in a PDAPP Mouse Model.

BACKGROUND: Alzheimer's disease (AD) is characterized with progressive memory loss and severe cognitive impairments, which affect everyday life and human health in the elderly. It is required that an effective and safe protective reagent against AD should be developed. It has been reported that humanin (HN) exerts neuroprotective effects against AD. In this study, we investigated the effect of a novel and more effective HN derivative, Colivelin (CLN) on AD. METHODS: PDAPP(V717I) transgenic AD model mice (derived from parental C57/BL6 mice) were used in our study as AD model. Morris water maze test was used to test the memory impairment of AD mice and the levels of Aß40 and Aß42 were determined by an Elisa assay. We used an Immunohistochemistry and Immunofluorescence staining method to check the GFAP and MAP2 positive cells, and TUNEL to assess the apoptotic cells. Western blot assay was used to check the expression and phosphorylation level of p38. RESULTS: We found that CLN improved the memory impairment induced by AD and reduced the deposit of Aß40 and Aß42. CLN also inhibited cell apoptosis and activation of caspase 3 in brain tissues of AD mice. Inflammation in AD mice was alleviated by CLN treatment, including the accumulation of GFAP positive cells and the inflammatory cytokines. With both structure of AGA-HNG and ANDF, CLN exhibited significantly stronger effects than synchronously administration of AGA-HNG and ADNF, suggesting CLN as a novel potential effective therapeutic reagent for AD patients. Finally, we found that CLN inhibited phosphorylation of p38 in AD mice and p38 inhibitor, SB203580 weakened the therapeutic effect of CLN. CONCLUSION: CLN effectively improved the memory dysfunction in PDAPP mice, and our data suggests CLN as a novel and effective reagent which may have great potentials in AD therapy.

Safety and Efficacy Analyses of Angioplasty and Stenting for Severe Intracranial Arterial Stenosis: A Single-Center Retrospective Study in China.

BACKGROUND: The value of percutaneous transluminal angioplasty and stenting (PTAS) in the context of aggressive medical treatment for severe intracranial artery stenosis (ICAS) is under debate. This study compared the effects of PTAS and aggressive medical treatment in patients with severe ICAS and transient ischemic attack or stroke. MATERIAL AND METHODS: A retrospective cohort study was performed. Patients with severe ICAS were assigned to a PTAS group or aggressive medical treatment group, according to the angiographic features of the stenotic lesions. The primary outcome was defined as stroke or death within 30 days or cerebral ischemia occurring ipsilaterally to the qualifying artery beyond 30 days. RESULTS: We included 220 patients: 48 in the PTAS group and 172 in the medical group. The median follow-up was 32 months. PTAS was not associated with an increased incidence of the primary outcomes (10/42 vs. 39/172, p=0.96) or increased risks of the secondary outcomes of stroke, cardiovascular events, major bleeding, or mortality. The results of log-rank tests did not support a significant difference in event-free survival as a primary outcome between the 2 groups (chi-square=0.07, p=0.79). Moreover, although not significantly greater, the mean survival of patients in the PTAS group appeared to be better than that among patients in the medical group, as indicated by the curve for cumulative survival. CONCLUSIONS: A suitable PTAS procedure is safe for patients with severe ICAS, and no significant differences in incidence of recurrent stroke or death were found between PTAS and aggressive medication treatment.